PCSK9 Inhibitor Evolocumab Reduces First Major Cardiovascular Events in High-Risk Patients Without Prior Heart Attack or Stroke

Adding the PCSK9 inhibitor evolocumab to a high-intensity, cholesterol-lowering regimen reduced the risk of a first major cardiovascular event among adults with atherosclerotic cardiovascular disease or diabetes, according to results from the international VESALIUS-CV clinical trial presented at the American Heart Association's Scientific Sessions 2025. The study found that among adults with atherosclerotic cardiovascular disease or diabetes and no history of a prior heart attack or stroke, evolocumab reduced the risk of coronary heart disease death, heart attack, or ischemic stroke by 25% over a median follow-up of more than four and a half years.

Participants taking evolocumab also had a 19% reduction in the risk of coronary heart disease death, heart attack, ischemic stroke or arterial revascularization. The trial results demonstrated that LDL-C lowering with evolocumab can reduce the risk of a first major cardiovascular event in patients at elevated cardiovascular risk but who have not had a prior heart attack or stroke. Lead study author Erin A. Bohula, M.D., D.Phil., noted that these results represent the first demonstration of improved cardiovascular outcomes with a PCSK9 inhibitor, or any non-statin medication, in patients without a previous heart attack or stroke who are already being treated with a high-intensity lipid-lowering regimen.

The study included 12,257 adults with an average age of 66 years, conducted at 745 health care sites in 33 countries including the U.S. between June 2019 and November 2021. Participants were eligible if they had an LDL-C of at least 90 mg/dL, met study inclusion criteria for atherosclerosis or high-risk diabetes, and had at least one other cardiovascular risk factor. At the start of the study, about two-thirds of participants met inclusion criteria for atherosclerosis without a prior heart attack or stroke, and 50% met inclusion criteria for diabetes.

Additional findings showed a 27% reduction in cardiovascular death, heart attack or ischemic stroke and a 36% reduction in heart attack among participants in the evolocumab group compared to placebo. Nominally lower rates of death from cardiovascular causes and death from all causes were noted in the evolocumab group compared to the placebo group. In a sub-study evaluating lipid measures over time, the median LDL-C at enrollment was 115 mg/dL, and at 48 weeks, LDL-C was lowered by nearly 55% in the evolocumab group, resulting in a median LDL-C level of 45 mg/dL, while LDL-C levels remained elevated in the placebo group at 109 mg/dL.

Bohula explained that the magnitude of cardiovascular benefit per unit of LDL-C reduction is similar to what has been observed in statin trials, as described by the Cholesterol Treatment Trialists' Collaboration available at https://www.ctsu.ox.ac.uk/research/meta-trials/cholesterol-treatment-trialists-ctt-collaboration. The researchers suspect this similarity is related to the longer follow-up in their study compared to prior, shorter PCSK9 inhibitor trials that may have underestimated long-term clinical benefit. The findings support the use of intensive LDL-C lowering to achieve targets of around 40 mg/dL to help prevent a first major cardiovascular event.

The study had several limitations, including that a small group of patients were not being treated with any cholesterol-lowering treatment at the beginning of the study, and future studies including adults from various racial and ethnic backgrounds are needed to confirm if these findings apply across diverse populations. The full peer-reviewed manuscript is simultaneously published in The New England Journal of Medicine at https://www.nejm.org. Evolocumab is FDA-approved to treat high LDL-C levels, though PCSK9 inhibitors may not be covered by some health insurance plans, which may present access barriers for some patients.